Stressed hepatocyte sustains alcohol-associated hepatitis progression by producing leukocyte cell-derived chemotaxin 2

Abstract

Background Neutrophil infiltration and hepatocyte damage are indispensable hallmarks in alcohol-associated hepatitis (AH), yet the underlying crosstalk between neutrophils and hepatocytes and its role in AH pathogenesis remain unclear. Objective We investigate the regulatory role of leucocyte cell-derived chemotaxin 2 (LECT2) in hepatocyte–neutrophil interaction and its impact on AH progression. Design We used bulk and single-cell RNA sequencing to identify hepatocyte-secreted factors targeting neutrophils. We analysed serum and liver samples from AH patients and employed genetically modified mice alongside in vitro studies. Results RNA-sequencing analysis identified several neutrophil chemokines that are elevated in hepatocytes from AH patients, including LECT2 whose role in AH remains largely unknown. AH patients exhibited increased levels of LECT2 in hepatocytes, positively correlating with the severity of AH. Ethanol-fed mice also exhibited elevated liver LECT2, which was abolished by inhibiting endoplasmic reticulum stress. Functional studies revealed that ethanol-induced liver injury was ameliorated in Lect2 -deficient mice but was exacerbated in mice with hepatic overexpression of Lect2 . Furthermore, LECT2 exacerbated ethanol-induced liver injury by promoting reactive oxygen species (ROS) through its interaction with prohibitin 2 (PHB2), a neutrophil membrane protein. By directly binding to PHB2, LECT2 disrupts the stable structure of PHB1/PHB2 heterodimerisation, consequently leading to PHB2 degradation, ROS accumulation, neutrophil activation and neutrophil extracellular trap formation. Moreover, therapeutic intervention of LECT2 via Lect2 shRNA ameliorated ethanol-induced liver injury. Conclusion Our studies identified a novel vicious cycle between neutrophils and hepatocytes through the LECT2–PHB2 interaction, presenting a promising therapeutic intervention by targeting LECT2 to mitigate AH in patients. Data are available upon reasonable request. The data that support the findings of this study are available on request from the corresponding authors.